Persistent pain is stressful and produces mood disturbances such as anxiety and impaired reward motivation. While exercise is widely agreed to be analgesic, rodent studies have generally employed highly stressful forced exercise paradigms that may not only produce stress-induced analgesia, but may also exacerbate co-morbid mood disturbances such as anxiety. In order to dissociate exercise-induced analgesia from stress-induced analgesia, we are comparing a non-stressful exercise paradigm (voluntary running on a running wheel) with a highly stressful exercise paradigm (forced running on a treadmill) in terms of pain, anxiety and impaired reward. We are also studying changes to brain areas that mediate these systems. To date, we have established that despite persistent hind limb pain, rodents voluntarily engaged in wheel running, up to 2 km per day. In these animals, voluntary exercise was analgesic. Furthermore, in conjunction with voluntary exercise, moderate weight control further attenuated pain. Weight control also had stress-reducing properties, as evidenced by increase heart rate variability and lower levels of plasma corticosterone. We are continuing to study the effects of exercise in persistent pain states. Specifically, now that we have determined that rats with persistent pain will indeed engage in voluntary running behavior, we will compare stressful and non-stressful exercise paradigms in terms of analgesia, anxiety and reward motivation. Using immunohistochemistry, we will label specific biochemical markers in various brain regions associated with pain and emotional regulation. We will also use Positron Emission Tomography, a brain imaging technique widely used in humans, to address potential effects of pain and stress on receptor binding in relevant brain regions. Together, these studies will allow us to better understand how exercise, specifically voluntary exercise, produces beneficial effects in persistent pain states.